Rep. Prog. Phys. 59 (1996) 128.

Printed in the UK

Biomedical sensors using optical bres

Anna Grazia Mignani and Francesco Baldini
Istituto di Ricerca sulle Onde Elettromagnetiche Nello Carrara, CNR Via Panciatichi 64, I-50127, Firenze, Italy

Abstract Optical techniques developed for sensing purposes proved to be essential in many application elds, ranging from aerospace, industry, process control, to security, and also medicine. The capabilities of these sensors are generally enhanced when a bulk-optical conguration is replaced by optical bre technology. In the past few years, research programmes and also the market for bre sensors have assumed a relevant role. This is undoubtedly due to the growing interest in optoelectronics, but also to the very satisfactory performance and reliability that optical bre sensors are now able to provide. This paper focuses on the advantages that optical bre sensors offer to the biomedical eld, recalls the basic working principles of sensing, and discusses some examples. This review was received in July 1995

E-mail address: mignani@iroe..cnr.it E-mail address: baldini@iroe..cnr.it 0034-4885/96/010001+28$59.50 c 1996 IOP Publishing Ltd

A G Mignani and F Baldini

Contents

1. Introduction 2. The basic working principle of sensing 2.1. Architecture 2.2. Main problems 3. Sensors for physical parameters 3.1. Pressure 3.2. Temperature 3.3. Blood ow 3.4. Humidity 3.5. Cataract onset 3.6. Radiation dose 3.7. Biting force 4. Sensors for chemical parameters 4.1. Bile 4.2. pH 4.3. Oxygen 4.4. Carbon dioxide 4.5. Lipoproteins 4.6. Lipids 4.7. New aspects and perspectives of chemical sensors 5. Spectral sensors 6. Conclusions Acknowledgments References

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Biomedical sensors using optical bres

1. Introduction In the medical eld, the opportunities offered by optical bres have always been advantageously exploited. In fact, the use of optical bres in medicine goes back to the sixties, when bre bundles were successfully pioneered in endoscopy, both for illumination and for imaging. Subsequently, cavitational laser surgery and therapy also beneted from bres, which proved to be the most exible, and a low-attenuation delivery system inside the ancillary channel of endoscopes, and inside the natural channels of the human body as well. More recently, and especially since 1980, a great deal of research in optical bres has been dedicated to sensing, and again the medical eld found good opportunities for developing very promising sensors. Two classes of clinical care procedures can be distinguished, in which conventional methods present some drawbacks: in vitro laboratory tests of blood or tissue samples, which means frequent sampletakings for continuous checking, thus placing the patient under stress. In addition, therapeutic intervention is delayed, and errors can also occur, due to sample handling and photodegradation; in vivo measurements of many physical and chemical parameters performed by electrical devices (thermocouples, CHEMFET, semiconductor or piezoelectric elements), which are fragile and expensive, and expose the patient to electrical connections. Fibre optic sensors (FOSs) overcome some of these drawbacks, owing to the well known inherent characteristics of optical bres: geometrical versatility, such as miniaturization, exibility, and lightness, which allow easy insertion in catheters and needles, and hence highly localized measurements inside blood and tissues; suitable material, glass or plastic, which is study, non-toxic and biocompatible, and can be used for continuous measurements; intrinsic safety for the patient, ensured by optical bre dielectricity and by the low light power used for sensing purposes. Furthermore, optical bres present low attenuation, so that long bre links can be used, if the electronics must be located far from the bedside; in this case, bres must be cabled, so as to avoid handling problems. Another property is the absence of crosstalk between close bres, which suggests housing different sensors in the same catheter. In some cases a single electro-optic unit can be utilized for all the sensors, naturally with an appropriate illumination, detection and signal-processing scheme. An overview of bre optic sensors for biomedical applications is given, with particular attention to the sensors developed for in vivo monitoring, and to the advantages that these sensors are able to offer in different elds of application such as cardiovascular and intensive care, angiology, gastroenterology, ophthalmology, oncology, neurology, dermatology and dentistry. Examples of FOSs are reviewed according to a classication in three main classes: sensors for physical parameters, sensors for chemical parameters and spectral sensors, for which spectral analysis is performed in order to know the state of health of a particular organ or tissue.

A G Mignani and F Baldini

2. The basic working principle of sensing The working principle of FOSs is based on the modulation of the bre-guided light produced in one of the optical properties (phase, intensity, wavelength, polarization state) by the parameter under investigation. The complexity of the electro-optical system, the type of components selected, and thus cost of the sensor are related to the operating principle. The ideal FOS for biomedical applications should possess the following characteristics: reliability, automatic or semiautomatic operation for use by operators who have little or no technical background, low-cost installation and maintenance.

These requirements limit the selection of the sensors operating principle and impose limitations to the complexity of the electro-optical system. FOSs for biomedical applications are mostly of the intensity modulation type, owing to the low cost of their components and the simplicity of their architectures. They can be either intrinsic or extrinsic, according to whether the intensity modulation is produced by the bre, which is sometimes modied, or by an external transducer connected to the bre (gure 1).

Figure 1. Working principle of intensity-modulated bre-optic sensor.

2.1. Architecture A FOS of the intensity modulation type can be viewed as a compact electro-optical module connected to the measuring probe by a multimode optical bre (gure 2). The module houses source(s), detector(s), and all the electronics for signal processing. The sources can be either lamps, lasers, LEDs, or laser diodes. Lamps and lasers require beam focus optics and holders for the bre alignment. If a halogen lamp is used, interferential or dichroic lters may also be necessary when the sensor has a specic operating wavelength. LEDs and laser diodes, the most compact, may be housed in special receptacles that are easily connected to the bre by commercial connectors. The most recent LEDs and laser diodes offer a wide variety of wavelengths. Laser diodes have a high emission power and can, in many cases, replace costlier and bulkier lasers. The detectors are normally PIN-type photodiodes, which are also housed in proper receptacles, sometimes with lters to provide spectral response. The electro-optical module provides modulation of the source and amplication of the detected signals. An analogue/digital interface that connects the electronic section to a

Biomedical sensors using optical bres

Figure 2. Sketch of the instrumentation of a bre-optic sensor.

can enhance system control and, in addition, is useful in calibration and in carrying out and recording measurements over long periods. For standard procedures that require no subsequent modication, a preprogrammed microprocessor can be used in place of a PC. The optical bre connection carries the light intensity from the source to the probe and returns the intensity modulated by the measuring parameter to the detector. Generally, bres having diameter larger than 100 m are used to maximize the sources coupling efciency. The bres can be all silica (AS) or plastic silica (PCS), either bare or cabled, according to application. The connection can be either single bre, in which case the bre serves for both lighting and detection, or two bre, in which case one bre serves for lighting and one for detection. The single-bre connection, which is evidently more compact and thus reduces probe dimensions, requires a device upstream of the bre that separates the lighting and detection channels. However, the beam divider should always be characterized by intrinsic low losses and crosstalk to avoid covering up the measuring signal and also impairing the signal-to-noise ratio. Often bi- or trifurcated bre bundles are used, with random distribution of the bres inside the bundle or with special distributions (linear, semicircles, concentric circles, etc). In such case, the source(s) and detector(s) are connected to the branches of the bundle and the common termination is connected to the measuring probe. The optical architecture can be either all bre or hybrid:
PC

In the all-bre architecture, all the optical components connected to the bre (X-, Y-, or star couplers, WDM, gratings, etc) are optical bre based and the components are connected simply and compactly with commercial type connectors; In the hybrid architecture, used when optical bre components with less than satisfactory characteristics are available, the miniaturized optical components, such as lenses, lters, gratings, mirrors, etc, must be specially aligned and connected.

A G Mignani and F Baldini

2.2. Main problems The main problems regarding intensity modulation

FOSs

are:

Sensitivity to light propagation. A problem common to all intensity modulation FOSs is sensitivity to propagation conditions. Since the information is contained in the intensity of the guided light, any modulation not correlated to the state of the measuring parameter upsets the measurement. For example, an incorrect interpretation can be caused by uctuations in the source or attenuations introduced by bre curvatures. To solve this problem, a reference system must be used to compensate for the undesired intensity uctuations, despite the increase in system complexity and thus the cost it entails. Source intensity uctuations can be offset by normalizing the measurement signal S with a reference signal R proportional to the source intensity. Other spurious uctuations such as those produced by propagation accidents can be offset by a lighting signal with two wavelengths, one of which is modulated in intensity by the investigated parameter and the other of constant intensity. Since they both travel on the same bre, their ratio provides a measurement devoid of propagation accidents. Insufcient lighting power. The main problem determined by active and passive optical components is insufcient lighting power in the FOS. This depends somewhat on the power emitted by the source, and also on the quantity and quality of the required passive components. The requisites of the source, i.e. compactness, adequate power, and suitable wavelength, are not always fullled, especially when a source that is visible or beyond the range of typical telecommunication wavelengths is required. The requisites of the optical components are compactness and the capacity of each to perform several functions. The number of passive components should be minimized by accurate assessment of system power requirements. Design and manufacturing specications. The probes require accurate workmanship and hand assembly and must be designed to produce a high back-transmitted signal simultaneously with a fast response time. Major requisites are optimized housing, miniaturization, seal, and transducer stability. Particular attention must be devoted to the requisites of biocompatibility: i.e. the probe must not adversely affect the body nor must be adversely affected by it. The latter consideration should not be taken lightly; in fact, often we think only about the dangerous effect that an invasive sensor can have on the human body, and do not consider that (especially in chemical sensors, where a chemistry is xed at the end of the bres) the local environment can notably impair sensor performance. 3. Sensors for physical parameters The physical parameters of medical interest that have been successfully measured by FOSs are mainly pressure, temperature, blood ow, humidity, as well as cataract onset, radiation dose and biting force. 3.1. Pressure Head trauma patients require continuous monitoring of intracranial pressure. During the post-operative and drainage monitoring phases, it is essential to know, respectively, the subdural and ventricular pressures, as well as the pressure waveform display. Non-optical

Biomedical sensors using optical bres

Figure 3. FabryPerot bre-optic pressure sensor.

instruments make use of catheters tipped with miniaturized piezoresistive or capacitive transducers, whose main drawbacks are long-term drifts, electrical-shock hazard, fragility and costliness. FOSs, being relatively easy to manufacture and therefore inexpensive enough to be disposable, overcome these drawbacks. In addition, they perform as well as or better than electric instrumentation. Main measurement requirements are: (i) a working range from 50 to 300 mmHg; (ii) a sensitivity of at least 0.1 mmHg; (iii) an accuracy of at least 1%; (iv) a at frequency response up to 1 kHz. Among the many proposed pressure FOSs, two types full the low-cost, high-performance requirements. One has a FabryPerot cavity at the bre tip [1, 2]; the other has a small diaphragm in front of the bre optic link [35]. The FabryPerot cavity for pressure sensing is a glass cube having a partially etched face, covered by a pressure sensitive silicon diaphragm (gure 3). The pressure, deecting the diaphragm, alters the cavity depth and thus the optical cavity reectance at a given wavelength. If an LED source is used, the spectrally modulated reected light can be split into two wavebands by a dichroic mirror. The ratio of the two signals provides a pressure measurement immune to the typical light level changes occurring in FOS systems. A sensor of this type, together with the complete intracranial pressure monitoring system, is currently available from the American company Innerspace [6]. The other pressure sensing approach, characterized by a diaphragm in front of the bre optic link, is based on the light intensity modulation of the reected light caused by the pressure-induced position of the diaphragm. Two schemes can give immunity to false uctuations: (i) a dichroic coating on the diaphragm and the dual-wavelength referencing technique, and (ii) a dual-beam referencing using a second bre optic path, which is joined to the pressure measuring bre link, but unaffected by pressure uctuations. The low-cost disposable FOS manufactured by the American company Camino Labs [7], which uses a bellow as a transducer, is interrogated by the intensity modulation technique with dualbeam referencing (gure 4) [8].

A G Mignani and F Baldini

Figure 4. Fibre-optic pressure sensor based on a mechanical transducer.

3.2. Temperature Fibre-optic thermometers are used when electrical insulation and EMI immunity are necessary [9]. The most relevant application involves tissue-heating control during MW or RF hyperthermia therapy for cancer treatment. For this application, conventional thermistors or thermocouples can perturb the incident eld and produce localized hot spots. Other applications of thermometry by bre-optic sensors are the mapping of thermal distribution in cancer phototherapy, patient monitoring during magnetic-resonance imaging, and cardiac-output monitoring by means of the thermodilution technique. The possibility of simultaneous monitoring with arrays of multiple sensors is also desirable. For these applications, the restricted working range 3545 C is sufcient, with a sensitivity of at least 0.1 C. Because of the many applications, bre-optic thermometers have been widely proposed, either using all-bre mechanisms [10], and transducers undergoing intensity [11] or wavelength modulation [12, 13], or operating in the time domain [14]. The bre optic thermometer commercialized by the American company Luxtron [15], one of the rst developed for this purpose (gure 5), performs time-domain measurements and stands out for technical performance and patient safety. UV light guided by the bre is used to excite phosphors xed at the bre end and uorescence decay-time is measured, which results temperature modulated and intrinsically down-lead insensitive as well. Other sensors based on a bre FabryPerot (FFP) cavity coupled at the bre tip [16, 17] and MID-IR bres used as pyrometers [18] are under development.

Figure 5. Luxtron 3000: an 8-channel bre-optic temperature sensor.

Biomedical sensors using optical bres 3.3. Blood ow

Laser Doppler owmetry is a powerful tool for vasomotion monitoring, and the use of optical bres enhances the possibility of both invasive and contact measurements. The basic scheme of bre-optic laser Doppler owmetry is illustrated in gure 6. The light of a HeNe laser is guided by an optical bre probe to the tissue or vascular network being studied. The light is diffusely scattered and partially absorbed within the illuminated volume. Light hitting moving blood cells undergoes a slight Doppler shift. The blood ow rate is derived by the spectrum-analysis of the back-scattered signal, which presents a ow-dependent Doppler-shifted frequency. Various types of probes have been developed, either using a single bre for illumination and detection, or one bre for illumination and two or three for detection [19]. An instrument that is widely used in the clinical practice is produced by the Swedish company Perimed (gure 7), which offers a wide selection of contact and endoscopic probes, with straight or angular tips, as well as with channels for liquid ushing [20]. Typical applications are in: (i) plastic and reconstructive surgery for monitoring ap quality; (ii) angiology for

Figure 6. Basic scheme of bre-optic laser Doppler owmetry.

Figure 7. PeriFlux PF3: the Perimed instrument for bre-optic laser Doppler owmetry.

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A G Mignani and F Baldini

locating atherosclerosis and occlusions; (iii) dermatology for testing several types of skin irritancies such as psoriasis, or produced by topical drugs or cosmetics; (iv) pharmacology for detecting vasoactive drugs and dose response. Endoscopic and needle probes are used for invasive and deep measurements, for example in gastroenterology and in vascular surgery, respectively. 3.4. Humidity A major requirement of intensive care is the continuous monitoring of breathing condition, i.e. the cough, sneeze, and breathing count. It should be possible to monitor from the nurses station so patients can be kept under observation without a nurse being physically at their bedsides. An optical bre with a moisture-sensitive cladding has been developed for this purpose. It is simple to use and has given good performance results. The cladding of the sensitive bre-section is a plastic lm doped with the umbelliferon dye, which is a moisturesensitive uorescent material under UV-pumping. The sensitive bre-section is placed over the patients mouth and laterally excited with a halogen lamp. Since the water vapour in human respiration exceeds that in the room, the patients expiration produces a uorescent signal which is detected by an electro-optical unit at the nurses station. This kind of monitoring is particularly useful in detecting abnormal breathing in bedridden patients [21]. Another very simple humidity FOS has been developed for the continuous monitoring of the respiratory rate. The sensor is based on the change of light reection at the bre end which is caused by a change in the condensed humidity from the airways during respiration. An optical bre is simply clasped inside the nostril. During inspiration, the air is dry and cool, and there is maximum backreected light. During expiration, a water lm deposits on the bre and the backreected light is reduced by about 50%, so that the respiration rate can be monitored. Sensor output thus consists of a rhythmic signal, the frequency of which represents the respiratory rate [22]. 3.5. Cataract onset A major ophthalmological application of FOSs is the recognition of the onset of eye lens opacication, commonly known as cataracts. Since, in addition to ageing, cataracts can be caused by diseases such as hyperglycaemia or injury such as exposure to radiations, the early detection of a warning condition is essential in preventing and testing the new therapies that are now becoming available. As opposed to current clinical diagnostic methods, which only detect cataracts when they are nearly irreversible, bre-optic monitoring makes detection possible at onset, in time for reversal. The eye lens is a waterprotein system composed of water ( 65 weight percentage) and proteins ( 35 weight percentage). About 10% of the proteins, called the albuminoid fraction, are insoluble, while the remaining 90% of soluble proteins are divided into , , and crystallins. Cataract onset is attributed to crystallin aggregation and can be recognized by periodic measurement of the crystallin dimensions. A powerful and versatile tool for measuring particle size distribution in uid systems is the Dynamic Light Scattering (DLS) technique. In this case, the Brownian motion of crystallins in the cytoplasm illuminated by a coherent light source produces temporal uctuations in the scattered light. The measured intensity autocorrelation function shows an exponential decay, whose decay constant is related to the hydrodynamic radius of the scattering particles. Cataract onset is recognized by DLS measurement of the -crystallin aggregation, since the -crystallins are of greater molecular weight and size, and thus scatter

Biomedical sensors using optical bres

11

more light than the - and -crystallins. The non-invasive optical bre probe is a stainless steel capillary (OD 5 mm) ending in a face plate which houses two monomode bres sloped at a xed angle with respect to the capillary axis (gure 8). One of the bres is coupled to a HeNe laser used for illuminating the scattering region inside the eye lens. The other collects the backward scattered light, which is measured by a photomultiplier and processed by a digital correlator. Intensity autocorrelation measurements show a nearly bimodal distribution of particle size, respectively corresponding to -crystallins and their aggregation. The probe can be easily incorporated into conventional ophthalmological instruments such as an applanation tonometer mount [2325].

Figure 8. Assembly for cataract onset monitoring by optical bres and Dynamic Light Scattering measurements.

In addition to allowing prompt, non-invasive monitoring of cataract onset, optical bres also enhance the efciency of the DLS technique. By providing a beam of small numerical aperture and dimensions, monomode bres are able to produce an extremely small angle of coherence, and hence an optimal spatial coherence factor ( 0.9), which would be difcult to obtain with bulk optics systems [26].

3.6. Radiation dose The success of radiotherapy is related to the on-line monitoring of the dose to which the tumour and the adjacent tissues are exposed. Conventional thermoluminescence dosimeters only provide off-line monitoring, since they determine the radiation exposure after completing irradiation. A short length of heavy metal-doped optical bre coupled to a radiation resistant bre is an optimal system for the continuous monitoring of radiation dosage in both invasive and non-invasive applications. The light propagating in the doped bre section undergoes an intensity attenuation in the presence of radiation, since the attenuation is nearly linear to the radiation dose. Differential attenuation measurement compensates for insensitivity due to cable and connector losses [27].

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3.7. Biting force A FOS for dentistry measures biting force, which is an essential parameter in studying disturbances of the masticatory system and in the case of patients with osseointegrated implants or dentures. Unlike conventional piezoelectric crystals, quartz crystals, and strain gauges, which are unsuitable due to the high conductivity of the oral cavity, optical bres are intrinsically safe. The FOS is constituted by a mouthpiece made of two stainless steel plates with a microbending FOS placed in between. The optical bre results squeezed in between two plates inducing a periodic deformation in the bre and giving a light intensity attenuation as the biting force increases. The system is managed by a personal computer with software providing display, zeroing, and calibration. The dynamic range is 11000 N with a resolution of 10 N, which is satisfactory for the application [28]. 4. Sensors for chemical parameters In bre-optic chemical sensors the light transported by the bre may be directly modulated either by the parameter being investigated (spectrophotometric sensors), or by a special reagent connected to the bre, whose optical properties vary with the variation in the concentration of the parameter under study (transducer sensors). The probe is often called optrode, as it represents an opt ical electrode. The main physical phenomena exploited for the realization of chemical sensors are uorescence and absorption, even if chemical optical bre sensors have been realized by exploiting other physical phenomena, such as chemical luminescence, Raman scattering, evanescent-wave coupling, and plasmonic resonance. 4.1. Bile The demand for FOSs for in vivo monitoring of foregut functional diseases is notably on the increase. The rst and, to-date, only FOS available on the market for such an area of application is the Bilitec 2000 (manufactured by Prodotec, Firenze, Italy, and commercialized by Synectics, Stockholm, Sweden), for the detection of enterogastric and nonacid gastroesophageal reuxes [29] which are considered to be contributing factors to the development of several pathological conditions such as gastric ulcer, chemical gastritis, upper dyspeptic syndromes, and severe oesophagitis. Under certain conditions, the enterogastric reux may also increase the risk of gastric cancer. Optical detection is based on the optical properties of bile which is always present in such reuxes [30]. Basically, the Bilitec 2000 (gure 9) utilizes the light emitted at = 465 nm and 570 nm (reference) by two LEDs, and an optical bre bundle that transports the light from the sources to the probe, (which is actually a miniaturized spectrophotometric cell whose external diameter is 3 mm) and from the probe to the detector. The instrument evaluates the logarithm of the ratio between the light intensities collected by the detection system. Since, according to the LambertBeer law, the difference in the logarithms measured in the sample and in pure water is proportional to the bilirubin concentration, said difference is related to the bile-containing reux in the stomach and/or oesophagus. The method has been validated on numerous patients by inserting the optical bre bundle into the stomach or oesophagus via the nasal cavity [31]. The sensitivity of the sensor is 2.5 mol/L (bilirubin concentration), and the working range is 0 100 mol/L. This range ts well with the range which can be encountered in the stomach or in the oesophagus: even if the bilirubin concentration in pure bile can be as high as 10 mmol/L, it is progressively diluted to its nal concentration in

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Figure 9. Bilitec 2000: the only instrument for the direct detection of gastric reuxes.

the reuxate by pancreatic enzymes, duodenal secretion and, lastly, by the gastric content. Clearly, the characteristics of the above mentioned sensor refer to in vitro tests; as for in vivo measurements, since the gastric content is inhomogeneous with both mucus and solid particles suspended, although the absorbance values could numerically express the bilirubin concentration, they can only make possible an approximate quantitative assessment of the overall bile reux concentration. In any case, the sensor is able to measure accurately the contact time between the reuxate and the gastric and/or oesophageal mucosa. 4.2. pH pH is a very important quantity; our knowledge of it, however, is strictly related to the diagnosis of the good working of many organs and parts of the human body. pH is generally detected by a chromophore which changes its optical spectrum as a function of the pH; absorption-based indicators or uorophores are used for this. 4.2.1. Blood pH. Real-time monitoring of pH in the blood should be always accompanied by measurement of the oxygen and carbon dioxide partial pressures, pO2 and pCO2 respectively. Continuous and real-time knowledge of these parameters is of paramount importance in operating rooms and intensive-care units, in order to determine the quantity of oxygen delivered to the tissues and the quality of the perfusion. Conventionally, these parameters are measured by benchtop blood-gas analysers on manually-withdrawn blood samples. In any case, signicant changes may occur in blood samples after their removal from the body and before measurement is carried out by means of a blood-gas analyser. Thanks to their ability to provide continuous monitoring, FOSs represent a welcome

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Figure 10. Fibre-optic probe based on phenol-red dye for blood pH monitoring.

improvement in patient management. Invasive sensors must full the following requirements: (i) they must be suitably miniaturized so as not to slow down blood ow and thus give rise to clotting; (ii) they must not be thrombogenic; and (iii) they must be resistant to platelet and protein deposit. Since deposit resistance is primarily related to the sensors shape and to its chemical and physical properties, probes with smooth surfaces and coated with materials such as anticoagulants, and antiplatelet agents (e.g. heparin) are commonly used. It is apparent that these conditions must be satised not only by pH sensors, but by all sensors inserted in the circulatory system. The rst pH sensor was developed at NIH (Bethesda, Maryland) and made use of phenol red as its acid-base indicator, covalently bound to polyacrylamide microspheres; such microspheres are contained inside a cellulose dialysis tubing (internal diameter: 0.3 mm) connected to two plastic bres (core diameter: 500 m). The probe was inserted into tissue or a blood vessel through a 22-gauge hypodermic needle (gure 10). The probe was tested in vivo on animals for the detection of extracellular acidosis during regional ischemia in dog hearts [32], of transmural pH gradients in canine myocardial ischemia [33], and of conjunctival pH [34]. The rst intravascular sensor for the simultaneous and continuous monitoring of pH, pO2 , and pCO2 uses three optical bres (bre diameter = 125 m), and was developed by CDI-3M Health Care (Irvine CA, USA) on the basis of a system designed and tested by

Figure 11. Sketch of the bre-optic probe for the in vivo simultaneous detection of pH, pO2 , and pCO2 in human blood.

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Gehrich et al [35]. The bres are encapsulated in a polymer enclosure, that also contains a thermocouple embedded for temperature monitoring (gure 11). pH measurement is carried out by means of a uorophore, hydroxypyrene trisulphonic acid, covalently bonded to a cellulose matrix attached to the bre tip. Both the acidic (exc = 410 nm) and alkaline (exc = 460 nm) excitation bands of the uorophore are used, since their emission bands are centred on the same wavelength (em = 520 nm). The ratio of the uorescence intensity for the two excitations appears to be relatively insensitive to optical uctuations. Measurements of pO2 and pCO2 are described in the following sections. The optoelectronic system consists of three modules, one for each sensor. A Xenon lamp (operating at 20 Hz), suitably ltered, provides illumination for the three modules. The light from the source is focused through a GRIN lens onto a prism beam-splitter and is coupled by means of a bre to the sensor tip, while the deected light is collected by a reference detector for source control. The returning uorescence is deected by the prism beam-splitter onto the signal detector through a lter selecting the uorescence light. A microprocessor processes all the detected signals, giving the read-out of the three measurands on a monitor. The described probe (OD = 0.6 mm) has been tested in vivo on animals [36, 37], exhibiting satisfactory correlation with data obtained ex vivo from electrochemical blood gas analysers. In clinical trials on volunteers in intensive care and on surgical patients, among the problems that have emerged with the use of intravascular optical bre sensors are: (i) the formation of a thrombus around the sensor tip which alters the value of all the analytes and (ii) the so-called wall effect which primarily affects the oxygen count since, if the bre tip touches the arterial wall, it measures the oxygen in the tissue, which is lower than arterial blood oxygen. These problems are clearly avoided in a system working in an extracorporeal blood circuit, developed by CDI-3M and available on the market since 1984. Figure 12 shows the connection between the bre link and the blood circuit. A disposable probe, which makes use of the same chemistry as the intravascular optrode previously described, is inserted on line in the blood circuit on one side and connected to the bre bundle on the other. The

Figure 12. Exploded view of the optrode of the CDI-3M blood-gas analyser for extracorporeal analysis.

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system is currently serving in open-heart measurements; more than 10 000 disposable probes are produced by CDI-3M monthly.

Figure 13. Intravascular probe with bent bre and side-window sample chamber.

Other intravascular-probe systems have been proposed by Abbott (Mountain View, CA) [38] and by Optex Biomedical (Woodlands, TX) [39], as the structure of the probe is similar to the CDI one previously described, i.e. three different multimode bres, each of which is associated with the specic chemistry and charged with the detection of a single measurand. In the Optex Biomedical approach, the conguration is somewhat different: each single bre is bent, and a side-window sample chamber is built up to contain the appropriate chemistry (gure 13). The use of plastic bres ensures that the bundle will not break during insertion, routine patient manipulations and removal. There are basically three advantages in this lateral conguration: (i) the real optrode does not suffer any mechanical stress during insertion through the arterial catheter, (ii) there exists the possibility of avoiding the wall effect by rotating the probe into areas where the blood ow is good, and (iii) there is an increased sensing-element washability in the presence of a thrombus or other fouling phenomena. A different approach, recently proposed but still not tested in vivo [40], makes possible simultaneous multi-analyte detection with a single bundle of imaging bres (1500 individual 10 m bres with an overall diameter of 400 m). Spatial discrimination is obtained by creating, at the distal end of the bundle, separate portions with different indicating chemistry obtained by means of the photopolymerization process. The same optoelectronic system is used for both photodeposition and detection (gure 14). The white light from a mercury Xenon lamp suitably collimated passes through a dichroic lter, is removed during the photodeposition and is replaced by a pinhole, followed by a microscope objective. By adjusting the pinhole size and objective magnication, it is possible to illuminate a given portion of the bre bundle distal end which is then dipped into a polymerization solution containing the appropriate uorophore (uorescein for pH and pCO2 and a ruthenium complex for pO2 ). Photopolymerization allows the immobilization of the uorophore only in the illuminated region. Detection of the return uorescent signal is performed by using appropriate excitation and emission lters for the different sensing spots, and a CCD camera. An image-process approach is necessary in order to discriminate between the responses coming from the different sensitive spots.

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17

Figure 14. Multianalyte detection with an imaging bre bundle: scheme of the optoelectronic system used for both optrode photodeposition and detection.

4.2.2. Gastric and oesophageal pH. The gastric and oesophageal pH is an important parameter for the study of the human foregut. Monitoring gastric pH for long periods (for example, 24 hours) serves to analyse the physiological pattern of acidity, provides information regarding changes in the course of a peptic ulcer, and makes it possible to assess the effect of gastric antisecretory drugs. In the oesophagus gastrooesophageal reux, which causes a pH decrease in the oesophagus content from pH 7 to pH 2, can determine oesophagitis with possible strictures and Barretts oesophagus, which is considered a preneoplastic lesion. In addition, in measuring the bile-containing reux, the bile and pH should be measured simultaneously, since the accuracy of bile measurements decreases by about 30% for pH < 3.5 due to a shift in the bilirubin absorption peak to lower wavelengths [41]. Current practice is to insert a miniaturized glass electrode mounted on a exible catheter into the stomach or oesophagus through the nostrils, an impractical system due to the size and rigidity of the glass electrode, as well as to the possibility of electromagnetic interference. FOSs eliminate these drawbacks, although the broad range of interest (from 1 to 8 pH units) requires the use of more than one chromophore, which thus complicates the optrode design and construction. Most likely this is why almost all the bre-optic pH sensors developed for biomedical applications have been proposed for blood pH detection, and why only a few have been proposed for the detection of gastric or oesophageal pH [42, 43, 44]. The rst sensor proposed for this application made use of two uorophores, uorescein and eosin, immobilized in brous particles of amino-ethyl cellulose xed on polyester foil. The sensor, characterized by a satisfactory response time (about 20 s), was only tested in vitro. First in vivo measurements have been performed only very recently [45, 46], but none of the proposed systems appears completely satisfactory. John Peterson proposed a sensor based on two absorbance dyes, meta-cresol purple and bromophenol blue, bound to polyacrylamide microspheres. The conguration of the probe is similar to the one for blood pH measurement previously described (gure 10): the dyed particles are enclosed in 300 m inside diameter cellulosic-dialysis tubing, attached to a 250 m diameter acrylic optical bre. The bre is connected to a laboratory optical system arrangement consisting of a lamp coupled to lters, a CCD spectrometer and a personal

18

A G Mignani and F Baldini

computer. The sensor was tested on samples of human gastric uid, and was also tested in vivo by inserting the optical probe into the stomach of a dog. The accuracy, better than 0.1 pH units, satises clinical requirements, but the response time is much too long, between 1 and 6 minutes depending on the pH step; such a long response time would prevent detection of any rapid change of pH, and makes the sensor useless for the detection of gastro-oesophageal reux in which pH changes are very often extremely rapid (less than 1 minute). Another sensor makes use of two dyes, bromophenol blue (BPB) and thymol blue (TB), to cover the range of interest. The chromophores, immobilized on controlled pore glass, are xed at the end of plastic optical bres: the distal end of the bres is heated and the CPGs form a very thin pH-sensitive layer on the tip of the bres. Figure 15 shows a sketch of the probe: four bres are used (two for each chromophore) and a Teon reector was placed in front of the bres. A small ne steel wire was used in order to have a better coupling of the modulated light. An optoelectronic unit, similar to that used for bilimetric monitoring, has been developed: it consists of two similar channels, separately connected with the bres carrying TB and BPB for the detection of pH in the range 1 3.5 and in the range 3.5 7.5, respectively. The use of light-emitting diodes as sources and of an internal microprocessor has made it possible to construct a truly portable sensor. In vitro accuracy was 0.05 pH units. On the other hand the in vivo accuracy is still not satisfactory since in some cases, a step of some tenths of pH is present between the response of the optical sensor and the pH electrode.

Figure 15. Sketch of the optical probe for in vivo gastric pH monitoring.

4.2.3. Tissue pH. Twin-bre probes are generally used for in vivo mapping of normal and tumoural areas by means of pH measurements, since malignant tumours induce a decrease in the pH of the interstitial uid and depression caused by the administration of glucose. Dual-wavelength uorometry using optical bres provides a new diagnostic tool for highly-localized measurements. A nontoxic pH-dependent indicator (uorescein derivatives) is injected in the tissues to be analysed, and the twin-bre probe illuminates the tissue and measures the uorescence intensities at 465 and 490 nm. The ratio of these uorescence intensities is related to the pH of the tissue, thus providing normal-neoplastic tissue-mapping [47, 48].

Biomedical sensors using optical bres 4.3. Oxygen

19

Together with pH, oxygen is surely the chemical parameter most investigated for in vivo applications, as its knowledge and continuous monitoring are very important in many elds, such as those of circulatory and respiratory gas analysis. 4.3.1. Blood oxygen. As outlined previously, a knowledge of the oxygen content in blood is essential in order to know how the cardiovascular and cardiopulmonary systems work. This measurement can be performed either spectroscopically by exploiting the optical properties of haemoglobin, the oxygen-carrying pigment of erythrocytes, or by using an appropriate uorophore, the uorescence of which is quenched by oxygen. Spectroscopic analysis. Oxygen saturation, i.e. the amount of oxygen carried by the haemoglobin (Hb) in the erythrocytes in relation to its maximum capacity, was the rst quantity measured with FOSs [49]. This parameter is measured optically by exploiting the different absorption spectra of the Hb and the oxyhaemoglobin (OxyHb) in the visible/near infrared region. Numerous artery and vein insertion models are now commercially available, for example the instruments made by Oximetric Inc., Mountain View, CA; BTI, Boulder, CO; Abbott Critical Care, Mountain View, CA. In the simpler version, reected or absorbed light is collected at two different wavelengths and the oxygen saturation is calculated via the ratio technique on the basis of the isobestic regions of Hb and OxyHb absorption. On the other hand, the presence of other haemoglobin derivates, such as carboxyhaemoglobin, carbon monoxide haemoglobin, methemoglobin and sulphaemoglobin, makes preferable the use of multiple wavelengths or of the whole spectrum, which allow their discrimination [5051]. Non-invasive optical oximeters, which calculate oxygen saturation via the light transmitted through the earlobes, toes, or ngertips have also been developed, primarily for neonatal care [52]. In this case, particular attention has to be paid to differentiating between the light absorption due to arterial blood and that due to all other tissues and blood in the light path. This implies the use of multiple wavelengths, such as the eight wavelength Hewlett Packard ear oximeter [53]. Such a drawback can be avoided by using a pulse oximeter. This original approach is based on the assumption that a change in the light absorbed by tissue during systole is caused primarily by the arterial blood. By an appropriate choice of two wavelengths, it is possible to measure non-invasively the oxygen saturation by analysing the pulsatile, rather than the absolute transmitted or reected, light intensity [5456]. The detection of blood absorbance uctuations that are synchronous with systolic heart contractions is called photoplethysmography. One application is in dentistry where, by means of a pulse oximeter, it is possible to obtain information on whether the pulp is vital or necrotic: the tooth is squeezed between the termination of an optical bre bundle and two reective prisms, to illuminate the tooth and to collect the light transmitted through it. The ratio between the recorded AC (at 0.5 Hz) and DC components of the detected signal at 570 nm constitutes the sensor output, i.e. the tooth plethysmogram. Vitality is indicated by a rhythmic plethysmogram; necrosis, by a random plethysmogram [57]. In another dental-pulp vitalometer, the oxygen saturation content of dental blood is obtained by an optical-bre probe placed in contact with the tooth that performs reectance measurements at 660 nm and 850 nm. The signal ratio is processed together with a non-optical plethysmogram signal from one of the patients ngers, which is used as a reference in determining the tooths blood pulse. The resultant tooth plethysmogram also contains information on oxygen

20

A G Mignani and F Baldini

saturation, thereby allowing pulp vitality to be assessed [58]. Spectrophotometric measurements performed directly on the skin tissue and on the organ surface provide essential information on the microcirculation in tissue and skin and on the metabolism of an organ, respectively [59]. For example, on-line monitoring of the oxygen supply in peripheral organs has considerable importance. It is apparent that a perfect and adequate perfusion of all the organism is basic to the safety of the patient. In the presence of pathological changes in the oxygen transport chain, the organism, by itself, decreases the perfusion in peripheral organs (e.g. skin, skeletal muscles, gut) in favour of central organs such as the brain and the heart (centralization). This mechanism is one of the most effective and important ones during different shock forms. Spectra from biological tissues are able to detect the beginning of centralization before any external, physical and more dangerous symptoms become visible. On the other hand, during the early stages of shock, such an alteration of oxygen transport does not occur homogeneously on the tissue surface: therefore, only bre optics offer a sufcient spatial resolution for immediate detection. A special algorithm is generally used, since the spectra of the Hb and its derivatives are unevenly distributed in a highly scattering medium, and thus are notably altered. With the spectrophotometer analyser developed by BGT (Uberlingen, Germany) [60], important parameters such as intracapillary haemoglobin oxygenation, intracapillary haemoglobin concentration, local oxygen uptake rate, local capillary blood ow, changes in subcellular particle sizes, and capillary wall permeability (via the injection of exogenous dyes) can be measured in real time. Light from a Xenon arc lamp illuminates the tissue via a bifurcated bre bundle. The back-scattered light, ltered by a monochromator, impinges a photomultiplier connected to a computer that records the spectra resulting from the biological tissue. Thanks to the use of bres, only small volumes of tissue are investigated, thus making possible the resolution of spatial heterogeneities. The instrument is able to record spectra of high quality even in moving organs.

Optrode analysis. The disadvantage of utilizing haemoglobin as an indirect indicator for the measurement of oxygen is its full saturation at 100 Torr: this fact prevents, for example, the use of this method in the case of the respiration of gas mixtures with an O2 content larger than 20% as routinely used in anaesthesia. Therefore the use of a chemical transducer becomes necessary in some cases. The rst optrode-based oxygen sensor was described by John Peterson, and makes use of a uorophore, perylene-dibutyrate, the uorescence of which is efciently quenched by oxygen [61]. The dye, adsorbed on amberlite resin beads, was xed at the distal end of two plastic optical bres with a hydrophobic membrane permeable to oxygen. The probe described was tested in vivo for the measurement of the arterial pO2 level in dog eyes [62]. Other optrodes have been developed and tested in vivo, all of them using a uorophore, the uorescence of which is quenched by oxygen. In the intravascular sensor developed by CDI, previously described, a specially synthesized uorophore, a modied decacyclene (exc = 385 nm, em = 515 nm), is combined with a second reference-uorophore that is insensitive to oxygen, and is incorporated into a hydrophobic silicon membrane that is permeable to oxygen. A new type of non-invasive sensor has been proposed to measure the local oxygen uptake through the skin. The direct measurement of the oxygen ow on the skin surface provides information regarding the oxygen ow inside the tissue, which can help physicians to diagnose circulatory disturbances and their consequences. Two optrodes, which make use of a ruthenium complex, measure the difference in oxygen pressure across a membrane

Biomedical sensors using optical bres

21

placed in contact with the skin. In vivo tests performed on the left lower forearm of a patient gave good results [63]. 4.3.2. Respiratory oxygen. A knowledge of the concentration of oxygen, as well as of many other gases, in exhalation analysis is very important, since it may provide important information on the correct metabolism of the human body. An optrode for the simultaneous detection of oxygen and carbon dioxide, potentially suitable for respiratory gas analysis, has recently been proposed [6465]. It makes use of two uorescent dyes dissolved in a very thin layer (13 m) of a plasticized hydrophobic polymer which is xed at the distal end of optical bres. A wavelength discrimination by appropriate interference lters makes possible the simultaneous monitoring of O2 and CO2 , as the emission wavelengths of the two uorophores are sufciently separated. 4.4. Carbon dioxide As for oxygen, the measurement of CO2 is capable of providing important information in regard to the working of the circulatory and respiratory systems. Its detection is based on the detection of the pH of a carbonate solution, since its acidity depends on the quantity of CO2 dissolved therein. Therefore, all optrodes developed for blood CO2 make use of the same dye utilized for blood pH detection, xed at the end of the bre and covered by a hydrophobic membrane permeable to CO2 . In the intravascular CDI system the uorophore, hydroxypyrene trisulphonic acid (the same one used in the pH optrode), is dissolved in a bicarbonate buffer solution which is encapsulated in a hydrophobic silicon membrane permeable to CO2 and attached to the bre tip. 4.5. Lipoproteins A knowledge of the lipoprotein content in the blood is of paramount importance, as this protein is the carrier of cholesterol. Epidemiological studies have indicated that a reduction in blood cholesterol levels signicantly reduces the risk of atherosclerosis, ischemia, myocardial infarction, and death. On the other hand, it has been well demonstrated that measuring the total cholesterol in the blood is not sufcient for predicting the risk of cardiovascular diseases; but a knowledge of the type of lipoproteins, which can be different in size, density and lipid and apolipoprotein composition is essential. For example, highdensity lipoproteins, the second largest carriers of plasma cholesterol, have been recognized as being able to remove cholesterol from tissue and, consequently, of being capable of carrying on a protective action against arterial disease. The use of optical bres allows an in vivo investigation of arterial lesions. Fluorescence spectroscopy with optical bres makes the imaging of the intimal surfaces of arteries possible. On the other hand, interferences from the whole blood make preferable the use of near-IR wavelengths in which such interferences are noticeably reduced. Collection of the many whole near-IR spectra from one location at a time has recently allowed the chemical analysis of arterial lesions in living tissues, with the aid of an appropriate processing of the data based on a new experimental clustering technique that uses a parallel vector algorithm [66]. Such an in vivo qualitative (recognition of the different types of lipoproteins) and quantitative (concentration evaluation) analysis appears fundamental both for monitoring changes in arterial wall composition and for testing important new hypotheses of lesion formation, growth, and regression.

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A G Mignani and F Baldini

One of the major dermatological requirements is knowing the condition of the skin, which can be roughly determined by monitoring the skins hydration state and, more precisely, by determining lipid content. The latter parameter is of special importance in studies of acne. An inexpensive bre-optic refractometer has been developed for both tasks. The sensor comprises a plastic bre with a short section stripped of its cladding, where it is bent into a U-shape. With the U-shaped tip on the skin, the skin surface acts as the bre cladding. Since the skin surface is not perfectly smooth, some gaps are created around the bre core. At probe contact, the gaps are lled with air, but during the time the probe is in contact with the skin, they ll up with skin moisture. Consequently, sensor output decreases with time, at a rate dependent on the hydration state. The skin moisture content is obtained in relation to pre-xed threshold values [67]. It has been noted that, the higher the lipid contents, the higher the light reection, thus reducing sensor output. This disturbance has been used for estimating lipid quantity, through comparisons of sensor outputs relative to defatted and unprepared skin. By comparing this difference with pre-xed values, the lipid content has been successfully monitored, with the experimental results in good agreement with those obtained using a traditional gravimetric technique [68]. 4.7. New aspects and perspectives of chemical sensors Almost all the chemical sensors described above were tested in vivo or are being tested. As already pointed out, some of them are available on the market, and are capable of providing satisfactory answers to clinicians requirements while others are still at an experimental stage. A recent survey has made evident the main areas in which in vivo chemical sensors would be helpful [69], as can be seen from table 1, which reports the results of this survey. The number in parentheses for each analyte is the number of physicians who answered the survey.
Table 1. Main clinical problems and related analytes for which a continuous in vivo monitoring should be performed. Clinical problem Diabetes mellitus Analyte

glucose (24), K+ (3), ketones (2), insulin (2), lactate (1), pH (1) Vital function monitoring in O2 (15), CO2 (10), pH (8), haemoglobin (3), K+ (2), glucose intensive care/anaesthetics/ (2), electrolytes (unclassied) (1), gases (unclassied) (1), prolonged surgery Na+ (1), osmolality (1), lactate (1) renal failure/monitoring dialysis urea (4), creatinine (2), K+ (2), atrial natriuretic peptide (1), pH(1)

Some of the required analytes are already being monitored on-line with FOSs, and have been described here. Other FOSs have been proposed and seem promising, although none has as yet undergone in vivo testing (glucose, potassium, urea, lactate). Glucose is surely the analyte most in demand, because its control is of vital importance in diabetic patients, and a glucose sensor is an integral part of an articial pancreas with its controlled insulin release. Patients affected by diabetes mellitus need a monitoring of blood glucose levels during the whole day; but so far, no continuous sensor is available, obliging

Biomedical sensors using optical bres

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patients to self-monitoring of their blood glucose by periodic sampling and to the use of chemistry reagent strips. Different approaches with bre-optics have been presented, but at the moment some problems for their in vivo utilization still exist. Reversible competitive binding of glucose with uorescence labelled-dextran for sugar binding sites of a lectin, concanavalin A [7071], has been proposed. The probe consists of an appropriate hollow bre, coupled to bre-optics, capable of preventing the exit of reagents, but permeable to glucose (selection made on the basis of the molecular weight). Problems still open are the lifetime of the probe and the response time. Another approach makes use of glucose oxidase, an enzyme that catalyzes the oxidation of glucose; by exploiting the enzymatic reaction, it is possible to indirectly monitor glucose levels with the measurement of oxygen [72] or pH [73]. Although sensitive and for some aspects satisfactory (for example, fast response time), this approach seems even more appropriate for laboratory diagnostics than for in vivo sensing, mainly due to the deterioration of the chemicals utilized, which strongly limits the lifetime of the probes. An interesting technique is the exploitation of properties of the glucose as an opticallyactive substance, and therefore one capable of inducing a rotation of linearly-polarized light. The amount of rotation, detected by measuring the phase shift of the output voltage of the signal detector, can be related to the glucose concentration. Although at the moment it is not used with optical bres, this optical method seems very promising and has already been tested for the non-invasive monitoring of the aqueous humour of the eye [7475]. The advantage of this plain spectrophotometric technique is apparent and enormous: detection of the analyte is made without chemical reactions; consequently, fouling problems caused by the biological medium are avoided, and the problem of the lifetime of the probe is eliminated. Identical advantages are presented by IR-spectroscopy. The advent of IR-transmitting bres provides the possibility of seeing, by means of bre-optics, the rotational/vibrational bands which univocally characterize each molecule. The use in biomedicine of infrared spectroscopy coupled with the use of IR bres for in vivo monitoring is now taking its rst steps, but preliminary tests are very encouraging. In vitro spectral analysis of human blood serum performed with IR-transmitting non-toxic silver halide bres connected to an FTIR spectrometer, has recently been proposed [76], making possible the simultaneous monitoring of cholesterol, urea, total protein, uric acid and calcium. Continuous monitoring of respiratory gases could be performed in situ by coupling IR-bres with tunable diode laser spectroscopy (TDLS). TDLS has recently been applied with good results for the determination of trace gases such as CO, CO2 , NH3 , CH4 , NO in the exhalation of both humans and animals [77]. 5. Spectral sensors
FOSs

are also used in in vivo applications for checking the optical properties of organs without the measurements being related to the detection of any denite chemical/physical parameters. Spectral analysis of tissue can provide important information on its health. Fibre-ring catheters are used for the spectral-autouorescence analysis of tissues during endoscopy. Tissue autouorescence, excited by an HeNe laser, is spectrally analysed in the 660 850 nm range. The differences in spectral distribution between normal, cancerous, and necrotic tissues allow for real-time diagnostics, without the necessity for biopsy. Stomach, bronchial, and lung tissues have been diagnosed by bre catheters that combine coherent bre bundles with custom bundles optimized for uorescence measurements [78].

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MID-IR bre-based systems have been tested for in vitro tissue spectra measurements, with evanescent bre probes coupled to Fourier Transform spectrometers. Such systems have demonstrated the possibility of recognizing differences in normal and malignant tissue spectra (kidney, stomach, lungs) [79] and their suitability for diagnosing atherosclerosis [80]. In dermatological applications, the erythema meter (gure 16) aids in quantifying erythema in allergy and irritancy testing, as well as in measuring UV-induced erythema. Skin colour is mostly the result of blood quantity and melanin content, the reectance of which modulations range between 520580 nm and 500700 nm, respectively. Skin colour measurements are performed by a bre-optic bundle coupled with a dual-wavelength reectometer, which measures the ratio of skin reectance at 555 nm, modulated by blood quantity, to 660 nm, melanin sensitive but not inuenced by blood quantity and hence used as a reference. The sensor head (OD 5 mm) can be equipped with two mechanical components for 45 and 0 no-contact measurements [81, 82].

Figure 16. Fibre-optic erythema meter.

In dentistry, tooth-colour matching is a constant problem in restorative dentistry. The many disadvantages of the conventionally-used method, which is based on the visual comparison of natural tooth colour with standard colours, can be overcome by using a bre-optic reectance spectrometer. Originally developed for tissue diagnosis, this sensor can be a great help in selecting the material that best replicates the appearance of natural teeth. A slender, exible PMMA bre-optic bundle is used to illuminate a portion of the tooth with white light, and guides the tooths reected light to a portable grating spectrometer. The reectance spectrometer can also be used for diagnosing gingiva by means of bent probe heads inserted in the patients oral cavity [83]. 6. Conclusions The FOSs described above have given good results in in vivo testing. Some of these are already commercially available, while others are being developed in response to demands from the medical profession and encouraging market studies. The utilization of FOSs is increasing continuously, and this fact makes it feasible to imagine their more and more widespread diffusion for in vivo monitoring. The possibility of FOSs, in some cases already exploited [2, 35, 40, 84, 85], of monitoring several parameters

Biomedical sensors using optical bres

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with a single instrument makes them still more competitive in comparison with the other techniques and is continuously encouraged by physicians, who greatly appreciate the possibility of having a multitest portable unit with low-cost disposable probes, that can be easily managed by both doctors and patients. Acknowledgments The authors are grateful to Professor Annamaria Scheggi for her many helpful discussions and constructive suggestions. Thanks are also due to Dr Klaus Frank, BGT, Uberlingen, Germany; Professor Harri Kopola of the University of Oulu, Oulu, Finland; Dr Gordon Mitchell of Future Focus, Woodinville, WA; Dr John Peterson of the National Institutes of Health, Bethesda, MD; Dr Mei Sun of Luxtron, Santa Clara, CA; and, lastly, to Professor Takashi Takeo of the Nagoya Municipal Industrial Research Institute, Nagoya, Japan, for providing illustrative material. References
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